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Should I start a family?
Pregnancy and multiple sclerosis is a massive topic. In this newsletter I scratch the surface and try and answer some of the questions you may have.
I am 36 years of age and single, but I am in a casual relationship with somebody I work with. I have had MS for 18 years and have developed secondary progressive MS. I have problems walking and can manage about 200m. I have bladder problems and cognitive issues. I am currently on fingolimod. I am considering falling pregnant. What would you recommend?
Prof G’s Opinion
The following is my growing list of questions I have put together to help people with MS to make an informed decision about starting treatment. This newsletter covers some of the complexities of pregnancy. For this patient, there are no easy answers.
What are the attributes of the specific DMTs or treatment strategies?
Will I be able to become a parent? What about pregnancy and breastfeeding?
What is the impact of having MS on pregnancy and having children?
MS affects mainly women during their childbearing years and, as a result, affects pregnancy, family planning and decisions about starting or extending your family. A lot of opinion on this subject is based on data that predates the current era of active treatment and the newer generation of disease-modifying therapies (DMTs). I will therefore try and address the many issues around this subject by answering several questions that have arisen in my MS practice over the years.
Does MS affect my fertility?
No, MS does not affect fertility. Women and men with MS are as fertile as people without MS. However, MS does not protect women and men from other causes of infertility. Fertility treatment may impact MS (see below). Please be aware that mitoxantrone, AHSCT (autologous haemopoietic stem cell treatment), and other chemotherapy treatments, e.g. cyclophosphamide, used off-label to treat MS may be toxic to ovarian and testicular function requiring egg and sperm banking before treatment.
Will pregnancy affect the course of my MS?
Yes, this has been observed at a group level, but it isn't easy to notice things in individual people with MS (pwMS). It is well known that attack rates drop during the second and third trimesters of pregnancy, and relapses rebound again in the first six months after delivery. However, it is still only a minority of women with MS who have post-partum relapses. Breastfeeding does blunt the post-partum rebound, but this is not absolute. Therefore, most neurologists now recommend starting or restarting DMTs soon after delivery to try and prevent post-partum relapses.
Overall at a population level, the more children you have, the better your overall prognosis. This effect is small and is based on studies done in the pre-DMT era. The effect may be due to the immunological effects of pregnancy that work like a DMT in MS. Immunologists have tried to understand this phenomenon to develop treatments to mimic the pregnancy state to treat MS.
Will I be able to breastfeed after delivery?
Yes, I see no reason why you can’t breastfeed if you have MS. However, certain DMTs do cross over into the breast milk and may affect the baby. These include teriflunomide, cladribine and S1P modulators (fingolimod, siponimod, ozanimod and ponesimod). Although monoclonal antibodies (natalizumab, ocrelizumab, ofatumumab, rituximab) crossover in small amounts, the levels are generally too low to affect the newborn. In addition, the level of the antibodies will likely be further reduced by the digestion of the antibodies as they are proteins in the baby’s intestinal tract.
Please be aware that most DMTs are licensed with no breastfeeding safety data hence the information in the SmPC (summary of product characteristics) is not the same as that given to you by neurologists and other HCPs. For example, for the fumarates (dimethyl fumarate and diroximel fumarate) state:
“It is unknown whether dimethyl fumarate or its metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue Tecfidera therapy. The benefit of breastfeeding for the child and the benefit of therapy for the woman should be taken into account.”
This is very unhelpful as their main metabolite, monomethyl fumarate, is a naturally occurring metabolite. Fumarate is also compounded with many other medications that are considered safe in pregnancy, e.g. ferrous fumarate, an iron supplement. This is why I tell my female patients on fumarates they can breastfeed without concern for their baby.
We usually don’t recommend alemtuzumab treatment during breastfeeding simply because the medication used to prevent Listeriosis and infusion reactions crossover into breast milk. In addition, the acute immunosuppression associated with alemtuzumab may increase the risk of breast infections. In general, I tell my female patients to breastfeed for 4-6 weeks to give the baby the health benefits of breastfeeding and then to start or be retreated with alemtuzumab after this period.
For cladribine, it is important not to breastfeed whilst being dosed with the drug and for ten days after the last pill. The recommended 10-day requirement is probably a bit long as cladribine is undetectable in the body after 48-72 hours. In my experience, the requirement of a 14 or 15-day gap (4 or 5 days of dosing plus an additional ten days) in breastfeeding is challenging; therefore, most women who want to be treated with cladribine either delay treatment until they have completed breastfeeding or only breastfeed for 4-6 weeks before stopping and being treated with cladribine.
I am aware that women often feel pressured into breastfeeding. However, if you are anxious about having MS rebound post-partum, it is not unreasonable to decide not to breastfeed and start or resume your DMT as soon as possible. The decision to breastfeed or not is a personal choice.
How long before I fall pregnant must I stop my DMT?
It depends on which DMT you are taking. Only the DMTs that are teratogenic or potentially teratogenic, i.e. can cause foetal malformations, need to be stopped before you fall pregnant. It is essential to give sufficient time for these agents to be eliminated from the body. Teriflunomide has a very long half-life because it is reabsorbed in the intestine and is eliminated slowly from the plasma. Without an accelerated elimination procedure, it takes eight months to reach plasma concentrations of less than 0.02 mg/l, which are considered safe. Remarkably due to individual variations in teriflunomide clearance, it may take up to 2 years. An accelerated elimination procedure with cholestyramine or activated charcoal can be used at any time after teriflunomide discontinues.
Teriflunomide accelerated elimination procedure
After stopping treatment with teriflunomide:
• cholestyramine 8 g is administered three times daily for 11 days, or cholestyramine 4 g three times a day can be used if cholestyramine 8 g three times a day is not well tolerated.
• alternatively, 50 g of activated powdered charcoal is administered every 12 hours for 11 days.
Following either of the accelerated elimination procedures, it is recommended to verify elimination by checking teriflunomide blood levels and a waiting period of one-and-a-half months between the first occurrence of a plasma concentration below 0.02 mg/l and planned fertilisation.
Due to the risk to the foetus with the S1P modulators, they are contraindicated during pregnancy. Before initiation of treatment, in women of childbearing potential, we do a urine pregnancy test. Women must use effective contraception during treatment and for two months after stopping treatment with fingolimod (Gilenya), for ten days after stopping treatment with siponimod (Mayzent), for three months after stopping treatment with ozanimod (Zeposia) and for seven days after stopping treatment with ponesimod (Ponvory).
A problem with stopping the S1P modulators is the potential for rebound disease activity, which is why most neurologists now prefer to transition people from one of these therapies onto another class of drug that is considered safer in pregnancy. This could be a switch to injectables (interferon-beta or glatiramer acetate), fumarates, anti-CD20 therapy, natalizumab or being treated with an immune reconstitution therapy (cladribine or alemtuzumab) before deciding to try and fall pregnant. The good news is that several DMT options are now available to women with MS wanting to fall pregnant.
I cover some of the issues related to anti-CD20 therapies in the MS-Selfie case study “wait to fall pregnant or start a DMT now?” (24-Jan-2022).
If I fall pregnant on a DMT, will this affect the baby?
This depends on which DMT you are on what you mean by ‘affecting the baby’. We most worry about teratogenic effects, which describe congenital malformations. Teriflunomide, S1P modulators and cladribine are generally classified as drugs that may be teratogenic, and hence precautions need to be taken so as not to fall pregnant on these agents. Teratogenicity or foetal malformations usually occur very early in foetal development, often before the woman knows she is pregnant; therefore, it is difficult to do anything about it when foetal exposure occurs. Despite this, even for women who are on these agents and fall pregnant, we don’t automatically recommend termination of pregnancy. We refer them to the high-risk pregnancy clinic so that they can discuss the options with an obstetrician. Many women continue their pregnancies with an uneventful outcome and a normal baby. On the other hand, some women choose to terminate their pregnancy.
A large amount of data from MS pregnancy registries and post-marketing surveillance indicates no increased risk of significant congenital anomalies or spontaneous abortions (miscarriages) after exposure to interferon-beta or glatiramer acetate. Most neurologists are, therefore, comfortable with their female patients falling pregnant on interferon-beta or glatiramer acetate, continuing the treatment through pregnancy and allowing their patients to breastfeed on these agents.
Fumarates (dimethyl fumarate [Tecfidera], diroximel fumarate [Vumerity]) are not teratogenic and are unlikely to have a negative impact on pregnancy outcomes. At present, the data from registries and post-marketing surveillance need to mature, i.e. become more extensive, before we can be confident that the fumarates are entirely safe. However, as these agents are prodrugs and converted to monomethyl fumarate, which is part of our metabolism makes, it is very unlikely that the fumarate will cause any problems. Therefore, I don’t have an issue with women falling pregnant on the fumarates and continuing them through pregnancy. Many neurologists, however, recommend stopping fumarates once the woman knows she is pregnant. This conflicting advice is based on the fact that we can’t be sure at this point in time that the fumarates are safe during pregnancy.
Will I be able to be a good parent if I become disabled from my MS?
This is a very difficult question to answer and depends on how disabled you are, the type of disabilities and whether or not you have support. For example, I have a few patients who were wheelchair users, or close to being wheelchair users, when they had children, and they managed to nurse and look after their children. On the other hand, I have a few patients with cerebellar problems who have found it very difficult to bathe, change and feed their babies due to poor coordination and tremor. In one case, the spouse and the patient's mother stepped in to help, and the baby is now a young teenager. The decision, therefore, to start or extend your family if you have more advanced MS needs to be discussed with your partner and, if necessary, to get an occupational therapist to assess you and go through all of the issues relevant to you becoming a parent. My take on this is that disability per se is not a reason not to have children, but it does raise issues about the child that needs to be considered. Some of you may disagree; some MS HCPs I have worked with in the past disagree with me. This explains why many patients I see with advanced MS have been recommended not to have children by their HCP. Again the decision to have children, or not to have children, needs to be taken by you and not your HCP.
If I become disabled or unemployed due to MS, will I be able to support my children?
Similarly, this is a very difficult question; the answer depends on your circumstances. In the modern era having children and supporting them is expensive, but most high-income countries have social safety nets to protect you and your children in times of adversity. As we now have effective DMTs that prevent or delay disability, the decision to have children is easier than it was in the pre-DMT era.
What is the risk of my children getting MS?
MS is not a genetic disease in the Mendelian sense that you pass on to your children with a well-defined inheritance pattern. However, genetic factors increase your risk of getting MS. In high-prevalence countries such as the UK, the lifetime chances of a woman developing MS is about 1 in 375 to 400, and for a man, it is close to 1 in 750 to 800. However, for a daughter whose mother has MS, the risk is close to 1 in 40, and for a son, it is lower than 1 in 80. In some studies, the latter risk is no higher than the background rate. If the father has MS, the risk of his daughter developing MS is about half the risk of mother-daughter pairing, i.e. 1 in 70. For a son of a father with MS, the risk is likely lower than this, but the results across studies are inconsistent.
Can I do anything to prevent my children from getting MS?
Based on the known and modifiable risk factors for MS, you should keep your children vitamin D replete. To do this, you will likely need to supplement your children’s vitamin D intake. For children less than two years of age, I recommend 600 IU of vD3 per day; for children 2-10 years of age, 2,000 IU/day; and children above ten years of age, 4,000 IU vD3 per day. The latter is the same dose we recommend for adults. Other modifiable risk factors are childhood and adolescent obesity and smoking. We estimate that about 15% to 20% of new or incident cases could potentially be prevented by eliminating obesity and smoking in the general population. I must stress that these interventions are based on studies that show associations between these risk factors and MS and may not necessarily be causal. I must also point out that most people with all the risk factors for getting MS will not get the disease. This implies that the development of MS involves other unidentified or random factors, or bad luck, that can’t necessarily be modified.
Am I more likely to need an assisted delivery because I have MS?
In pwMS, who are not disabled, the answer is no. However, the more disabled you are, the more likely you are to have an assisted delivery or caesarian section. I suspect the latter may be due to fatigue and a lower threshold for the obstetric team to intervene in labour in people who are more disabled. I would recommend discussing your plans about the type of delivery you would like with your midwife and obstetrician.
Will I be able to have a standard vaginal delivery?
Yes, you will be able to have a standard vaginal delivery like other women, unless you have a well know contraindication to a vaginal delivery. The exception is women with MS with significant disability (see above), but even then, a standard vaginal delivery is possible. Please discuss this with your midwife and obstetrician, who are in a better position to give advice and help you formulate a plan. I see no reason, providing there are no contraindications, to have a trial of labour, and if it fails, you can have an intervention such as a caesarian section.
Will I be able to have an epidural during labour?
Yes, you will be able to have an epidural and other standard pain-relieving measures during labour. I am aware that in the old literature people with advanced MS did not tolerate spinal anaesthesia very well, i.e. they were reported to have a slow and incomplete recovery of function afterwards. This is something the anaesthetist should be aware of. Occasionally, an epidural need to be converted to a spinal anaesthetic if the epidural needle pierces the dura surrounding the nerve roots at the base of the spine.
How do you treat morning sickness or hyperemesis gravidarum during pregnancy?
The treatment of morning sickness or hyperemesis gravidarum is no different in women with MS than in the general population. It involves hydration, vitamin supplements, in particular thiamine, and the judicious use of antiemetics. The latter includes cyclizine, prochlorperazine, promethazine, chlorpromazine, metoclopramide and domperidone. If the vomiting extends into the second-trimester ondansetron can be used. In very severe cases of morning sickness, steroids may be required, for example, hydrocortisone 100mg twice daily that can then be converted to prednisolone 40-50mg daily by mouth, which can then be tapered to the lowest level, which still controls symptoms. For patients on one of the fumarates (the only oral DMTs safe in pregnancy), I would recommend to try and shift taking your medication to later in the morning when you are less likely to vomit.
Should I continue taking my other drugs for my MS symptoms during pregnancy?
Yes and no. It depends on what the medications are for and whether they are safe during pregnancy. Ideally, you would like to wean any symptomatic therapies or at least change to an alternative that are safe to take during pregnancy. This is why it is important to try and plan your pregnancy and, if necessary, be referred to a special medical or neurology pregnancy clinic so that these issues can be addressed. Please be aware that so-called neurology pregnancy clinics are not that well established, but they are increasing in number.
As far as physical therapies, these should be continued during pregnancy. One could argue that everyone with MS should be physically active and do pelvic floor exercises. Pregnancy and childbirth may impact bladder and bowel function hence it is important to see a pelvic floor therapist to start pelvic floor exercises if you have not done so already. Pelvic floor execises are taught to women in antenatal classes.
I also want to stress that many women with MS describe their MS-related symptoms improving during pregnancy. Many find they can do without symptomatic therapies. However, unless you are prepared to wean yourself off symptomatic therapies, you won’t know.
What is the best treatment strategy for my MS? Should I go onto a DMT and get my MS under control before starting a family or should I first start my family?
In principle, I don’t think wanting to start or extend your family should change the way you want to have your MS managed. Early effective treatment, treating to a target of NEIDA (no evident inflammatory disease activity), potentially flipping the pyramid, preventing end-organ damage and the holistic management of MS are all compatible with pregnancy. There are no rules on how to implement this strategy in pregnancy, because decision-making has to be personalised. For example, a woman with rapidly evolving severe MS may choose natalizumab and stay on it throughout pregnancy, including during breastfeeding, because her MS was so active and devastating she is not prepared to take a chance of having a further attack. Another woman who is young, with a very good prognostic profile and who is risk-averse may choose to delay starting a DMT until she has had a child. Another woman diagnosed at 40 may want to avoid any treatment that may delay her attempting to fall pregnant and opt to start a DMT that is safe in pregnancy.
In general, in women with active MS, I would recommend delaying pregnancy until their MS disease activity is under control, optimising their general health and preparing properly for pregnancy and becoming a parent. There is no point in having active MS, not starting a DMT and having a catastrophic relapse in the period during which you are trying to fall pregnant. I have a few examples of this in my practice.
I think it is up to the person with MS, their partner and sometimes their extended family to decide how they want their MS to be treated and managed during pregnancy. The HCP should be there to provide information and guide them in the decision-making process.
How is a relapse managed during pregnancy and breastfeeding?
If a relapse during pregnancy occurs, a short course of high-dose corticosteroids can be considered. However, I limit using steroids to disabling and severe relapses, especially early in the first trimester, as there is a potential but small risk of orofacial abnormalities (cleft lip and palate) and reduced birth weight from exposure of the developing foetus to high-dose of steroids. There is also a risk of precipitating gestational diabetes with high doses of steroids during pregnancy. In the rare situation of a severe relapses that are unresponsive to high-dose steroids, plasma exchange may need to be considered.
Methylprednisolone is transferred into breast milk. However, the amount transferred into breast milk is low, i.e. the relative infant dose is less than 1%. Given the short duration of pulsed steroids used to treat relapses, infant exposure is low. I am aware that some clinicians recommend women breastfeed before the infusion and then express breastmilk 1-2 hours after the infusion and discard it to limit exposure of the baby to methylprednisolone. I don’t think this is necessary.
Will neutralising anti-interferon beta antibodies (NABs) affect my baby?
There is a theoretical risk that neutralising anti-interferon beta antibodies may affect the baby. As only one human interferon-beta exists, NABs to therapeutic interferon-beta will neutralise the body’s natural interferon-beta. Interferon-beta is essential for innate immunity, and neutralising your interferon-beta may put you at risk of getting viral infections. I have looked after a patient who developed persistent reactivation of genital herpes virus infections that coincided with her developing NABs to interferon-beta. To control the herpes infection, we had to put her on continuous antiviral medication, which was done on the advice of a virologist. She has now been on famciclovir prophylaxis for over a decade, and every time she stops the famciclovir, her genital herpes reactivates. Interestingly, and not unexpectedly, she has remained NAB postive.
Interferon-beta does play a role in foetal bone development, however, as the placenta only matures in relation to immunoglobulin transfer towards the end of the second trimester of pregnancy, it is unlikely that sufficient NABs cross the blood-placental barrier to affect foetal bone development. However, in the third trimester, NABs will cross over the placenta into the foetal circulation and may impact the baby's innate immunity. Despite these theoretical concerns, there is no indication from published data to support these potential adverse effects of NABs.
Can I have IVF, and what will IVF do to my MS?
There is no reason why a person with MS cannot have IVF. However, there appears to be a slightly increased risk of relapse after IVF and egg harvesting. Whether this is due to stopping DMTs before undergoing IVF or due to the drugs used to stimulate ovulation is a moot point. Another factor is publication bias, in that studies reporting an increase in disease activity after IVF are more likely to be published than studies not showing an increase in disease activity. Because of this, I now recommend treating IVF as a planned pregnancy and giving women with MS the option of being on DMT which is relatively safe in pregnancy or treating their MS with IRT (immune reconstitution therapy) before IVF.
What dose of vitamin D do you advise during pregnancy?
During pregnancy, vitamin D requirements are increased, and I recommend doubling the dose for supplementation from 4,000 IU of vitamin D3 to 8,000 IU per day. At the same time, women who are pregnant should be on iron and folate supplements that should ideally be started before falling pregnant.
Are oral contraceptives safe in people with MS, and which contraceptive would you recommend?
To the best of my knowledge, contraceptives are safe and effective in women with MS. The same contraindications and relative contraindications to specific contraceptives apply to women with MS as in the general population. As you are aware hormonal contraceptives are associated with a higher risk of thrombosis, e.g. deep vein thrombosis, and in women with MS who are immobile, the risk of DVT is higher.
In my experience, MS should not be deciding which contraceptive to use. The exception may be in women with MS who are more disabled, where managing menstruation and menstrual hygiene may be a factor, and contraceptives that suppress menstruation have advantages, for example, continuous hormonal contraceptives or the progestin-tipped intrauterine contraceptive device (Mirena coil).
I am aware that conditions to participate in specific drug trials sometimes mandate you to use double contraception, such as a hormonal contraceptive and a barrier method. The latter, however, is to try and avoid accidental pregnancies on investigational compounds without a safety track record in humans.
Please feel free to share your experiences with the community and to ask pregnancy questions I haven’t addressed in this newsletter. The issues raised above show you how complex the management of MS has become, which is why there is a push for pwMS to be managed in specialist MS units. Do you agree?
You may find the following review of managing pregnancy in women with MS helpful.
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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust. The advice is intended as general advice and should not be interpreted as personal clinical advice. If you have problems, please tell your healthcare professional, who will be able to help you.